CC BY
10
Vestnik FEB RAS. 2018. № 6 Supplement
UDC 547.996+593.9 DOI: 10.25808/08697698.2018.202.6S.025
A.S.SILCHENKO,V.I. KALININ, S.A. AVILOV
Structural diversity
and some biosynthetic peculiarities
of triterpene glycosides
from the sea cucumbers
Key words: sea cucumbers, triterpene glycosides, biosynthesis.
Sea cucumbers (class Holothuroidea) are the marine invertebrates belonging to the phylum Echinodermata biosynthesizing unusual for other animals metabolites - triterpene glycosides. The lanostane aglycones and carbohydrate chains comprise the molecules of triterpene glycosides. There are some structural types of the aglycones: holostane type (lanostane derivatives with 18(20)-lactone) and non-holostane type, which is subdivided into groups having 18(16)-lactone or lacking a lactone. There are also the aglycones with shortened or normal side chains within each group of the aglycones. Carbohydrate chains of these compounds differ from each other by the diverse monosaccharide residues composing them, by the number and sequence of the residues and therefore by the architecture. Some of the sugar chains contain from one to three sulphate groups.
The applying of modern techniques of isolation and structural elucidation allowed the discovering of some minor glycosides possessing very interesting structural features. Some glycosides are characterized by unusual aglycones [1 and references herein]. Among them are: synaptoside A from Synapta maculata having 7-keto-8(9)-en fragment in holostane aglycone,
* SILCHENKO Alexandra Sergeevna - PhD, Senior Researcher, KALININ Vladimir Ivanovich - DSc, Leading Researcher, AVILOV Sergey Alexandrovich -DSc, Leading Researcher (G.B. Elyakov Pacific Institute of Bioorganic Chemistry, FEB RAS, Vladivostok, Russia). *E-mail: alex@piboc.dvo.ru
The work was supported by RFBR grant № 16-04-00010.
cucumariosides A8 and A9 from Eupentacta fraudatrix having unique 18,20-dihydroxy fragment in the aglycones without lactone ring, cucumarioside A12 from the same sea cucumber and 27-nor-25-oxo-holotoxin A1 from Psolus fabricii the representatives of very rare 27-nor-triterpenoids; cucumarioside H8 from E. fraudatrix and magnumoside A1 from Massinium magnum having unique 16(22)- and 20(24)-epoxy-groups in the aglycones, correspondingly; unprecedented octanorlanostane aglycone of cladoloside C4 from Cladolabes schmeltzii. Finally, the series of glycosides (fallaxosides) with uncommon aglycones was found in the sea cucumber Cucumaria fallax. Majority of them contained non-holostane aglycones without lactone having 8(9)-double bond and oxygen-containing functionalities at C-7 and C-11. Two compounds - fallaxosides B1 and D3 characterized by unprecedented rearranged lanostane carbocyclic systems in their aglycones. The first of the above has an 18(16)-lactone and additional 16,23-five-membered cycle; the latter has no a double bond, a lactone ring and a side chain and contain two cyclohexane and two cyclopentane rings and a spiro carbon.
The pathways of biosynthetic transformations of these unique aglycones were suggested. Thus fallaxoside B1 was formed as a result of an enzymatic intramolecular aldolic condensation of 1,6-diketo precursor leading to the formation of additional C-23-C-16 covalent bond. The formation of fallaxoside D3 was explained by the proton induced Meinwald or pinacol-pinacolone-like rearrangement of 8,9-epoxy or 8,9-dihydroxy precursor, correspondingly, that leads to shifting of 7(8)-covalent bond to 7(9)-position with a size decreasing of cycle B to five-member one and formation of spiro-quartenary center between the rings B and C and a keto group at C-8 position [3].
Some uncommon structural features were also found in carbohydrate chains of the glycosides. The glycosides of Synapta maculata were characterized by pentasaccharide sulphated carbohydrate moiety, containing 3-O-methylglucuronic acid, which was found first in the glycosides of sea cucumbers. Moreover it does not occur in the glycosides from plants or sponges but comprises the capsule polysaccharides of bacteria. The sugar chains of the glycosides from Staurocucumis turqueti and S. liouvillei contain rare 3-O-methylquinovose residue that is considered as chemotaxonomic character of the genus Staurocucumis. Cucumariosides of the group B from E. fraudatrix and colochiroside E from Colochirus robustus, correspondingly, contain linear and branched trisaccharide chains. Cladoloside N from Cladolabes schmeltzii has three xylose residues (as first, second and third units) and cladolosides of the groups F and H have two quinovose residues (as second and fifth units) in the carbohydrate chains. High-polar glycosides with sulphated hexasaccharide sugar chains were first discovered in the same sea cucumber. Some of cladolosides were characterized by the presence of non-methylated sugars as terminal units in hexasaccharide chains. Colochiroside E from C. robustus, cladoloside J1 from C. schmeltzii, psolusoside B from Psolus fabricii and kurilosides A and C from Thyonidium kurilensis were characterized by the unusual architecture of sugar chains.
So, having the data array concerning the structural diversity of triterpene glycosides from the sea cucumbers, we can analyze their biogenetic relationships and biosynthetic pathways. The species Eupentacta fraudatrix and Cladolabes schmeltzii are convenient objects for the analysis of carbohydrate chains biosynthesis since the high diversity of these parts of their glycosides. The synthesis and elongation of glycosides sugar moieties occur through the consequent attachment of monosaccharides to the certain positions of the forming chain. The sulphation is frequently considered as a final stage of sugar chain biosynthesis.
The glycosides of E. fraudatrix - cucumariosides of the groups A, B, C, D, F, G, H and I, contain trisaccharide, tetrasaccharide and pentasaccharide chains with or without sulphate groups [2 and references herein, 4]. Cucumariosides of the group A - linear nonsulphated tetraosides could be considered as "basic" group which is actively transformed in the process of biosynthesis. Its sulphation leads to the formation of the chains of cucumariosides belonging to the groups G and F and its subsequent glycosylation by C-2 of quinovose resulted in the formation of cucumariosides of the groups H and I. The formation of cucumariosides of the group C occurred by glycosylation of sugar chain of cucumariosides of the group A without prior
sulphation. So, sulphation and glycosylation are the alternative processes leading to the synthesis of different groups of cucumariosides. The minor triosides - cucumariosides of the group B also could be the biosynthetic precursors of pentaosides belonging to the groups of cucumariosides C, D, H and I when the glycosylation by C-2 of quinovose precedes the glycosylation by C-4 of this residue. Thus the biosynthesis of glycosides carbohydrate chains in E. fraudatrix is a mosaic type as its different stages can be shifted in relation to each other in time (heterochrony) and proceed in different consecutions. The result of such mosaicism is the formation of final products (sulphated pentaosides) by different (alternative) pathways.
А
OH i
O glycosylation by C-4 of Quin
CH2OH , >—oj^^^-O. O
/-Ov O
C^-T
ch2oh ' O O
chl„ o i£>
glycosylatio by C-2 of
cucumariosides of the group G
NaO3SO CI
CH2OH /oh
<o0o
o г
АГЛ
chlo o
>SO3N^^H S
O O OH
cucumariosides oh of the group F
Агл
NaO3SO CI
ch2oso3n^oh
o T
cucumarioside D
oHoVoOHU>
OH OH OH
cucumariosides of the group A А™
(■'V—O o
<or\i oh ™ "T^H <£_;>
cucumariosides cuMm«™*» oH*—Г
cucumariosides of the group H
cucumariosides of the group I
The glycosides of sea cucumber C. schmeltzii are characterized by the extreme diversity (19 types) of carbohydrate chains. When analyzing their biogenesis it becomes obvious that each type of chain is biosynthesized by one pathway only as individual consequence of the glycosylation reactions. So this situation is opposite to that observed in E. fraudatrix. The first step of diversification of biosynthetic pathways of cladolosides occurs after the formation of xylosides of the aglycones. The mainstream of biosynthesis is the glycosylation of the first xylose residue by the quinovose leading to the formation of all the cladolosides with one exception (the attachment of another xylose unit occurs in the process of cladoloside N formation). All consistencies of glycosylation reactions pass through the branching points. At the most branched point cladolosides of the group A with tetrasaccharide chains are located similarly to cucumariosides of the group A in E. fraudatrix.
The sulphation of cladolosides always occurs in final biosynthetic stages since sulphate group attaches to terminal methylated monosaccharide residues of penta- and hexasaccharide chains. The methylation of sugar chains is a "termination signal" stopping further elongation of a chain. The presence in some groups of cladolosides of non-methylated terminal residues indicates the attachment of O-methyl directly to synthesizing sugar chain, but not to the monosaccharide that consequently glycosylates forming chain. However in cladolosides 3-O-methylation in not
sulphation
cladoloside G cladolosides
+SO3Na ^ of the groups K, L
i+Me cladolosides
always a final stage for the whole molecule because after the introduction of this termination group to one half-chain (upper or bottom) elongation of another half-chain could proceed. The time shifting of these stages relative to each other (heterochrony), characteristic for the mosaic type of biosynthesis, lead to the formation of carbohydrate chains with terminal residues with or without 3-O-methyl group in the fourth or sixth positions of the chains.
Thus, comparison of metabolic networks of carbohydrate chains of the glycosides from E. fraudatrix and C. schmeltzii showed different degree of mosaicism of their biosynthesis. Classical mosaic type of biosynthesis is inherent for the sugar moieties of E. fraudatrix. Whereas biosynthesis of carbohydrate parts of glycosides in C. schmeltzii has more regulatory (strictly directed) nature but with some character traits of mosaicism.
REFERENCES:
1. Mondol M.A.M., Shin H.J., Rahman M.A. Sea cucumber glycosides: chemical structures, producing species and important biological properties // Marine Drugs. 2017. V. 15. 317 P. 1-35.
2. Popov R.S., Ivanchina N.V., Silchenko A.S, Avilov S.A., Kalinin V.I., Dolmatov I.Y., Stonik V.A., Dmitrenok P.S. Metabolite profilling of triterpene glycosides of the Far Eastern sea cucumber Eupentacta fraudatrix and their distribution in vatious body components using LC-ESI QTOF-MS // Marine Drugs. 2017. V. 14. 302. P. 1-17.
3. Silchenko A.S., Kalinovsky A.I., Avilov S.A., Dmitrenok P.S., Kalinin V.I., Berdyshev D.V., Chingizova E.A., Andryjaschenko P.V., Minin K.V., Stonik V.A. Fallaxosides Bt and D3, triterpene glycosides with novel skeleton types of aglycones from the sea cucumber Cucumaria fallax // Tetrahedron. 2017. V. 73. P. 2335-2341.
4. Silchenko A.S, Kalinovsky A.I., Avilov S.A, Popov R.S., Kalinin V.I., Andrijaschenko P.V., Dmitrenok P.S, Yur-chenko E.A. Triterpene glycosides from the sea cucumber Eupentacta fraudatrix. Structure and cytotoxic action of cucumarioside D with a terminal 3-O-Me-glucose residue unique for this species // Natural Product Communications. 2018. V. 13, No. 2. P. 137-140.
